In vivo confocal microscopy qualitative investigation of the relationships between lattice corneal dystrophy deposition and corneal nerves

Background To investigate the corneal neurotropic phenomenon in patients with lattice corneal dystrophy (LCD) with in vivo laser scanning confocal microscopy (IVCM). Methods IVCM was performed on a total of 15 patients (28 eyes) with LCD annually at a follow-up. A collection of the data was acquired to be analyzed. Results As indicated by the analysis, the LCD patients’ normal corneal stromal nerves (Grade 0) presented a decline with the prolongation of the follow-ups, corresponding to a gradual increase in grade I and II involving amyloid-wrapped nerve fibers, which demonstrated that the growing amount of amyloid deposit due to the corneal nerve invasion increased slowly over time. Conclusions The neurotropic phenomenon could increase with its severity in the corneal lesion of the patients with LCD, and also reflect the distribution of the corneal nerves, to some extent. IVCM provides a rapid, noninvasive way to observe the corneal nerves, which can be an efficient means of better understanding the development of LCD.

Image-level trajectory inference of tau pathology using variational autoencoder for Flortaucipir PET

PurposeAlzheimer’s disease (AD) studies revealed that abnormal deposition of tau spreads in a specific spatial pattern, namely Braak stage. However, Braak staging is based on post mortem brains, each of which represents the cross-section of the tau trajectory in disease progression, and numerous studies were reported that does not conform to this model. This study aimed to identify the tau trajectory and additionally quantify the tau progress in a data-driven approach using the continuous latent space learned by variational autoencoder (VAE). Methods1080 [18F]Flortaucipir brain PET images were collected from Alzheimer’s Disease Neuroimaging Initiative database. VAE was built to compress the hidden features from tau images in latent space. Hierarchical clustering and minimum spanning tree were applied to organize the features and calibrate them to the tau progression, thus deriving pseudo-time. The image-level tau trajectory was inferred by continuously sampling across the calibrated latent features. We assessed the pseudo-time with regards to tau standardized uptake value ratio (SUVr) in AD-vulnerable regions, amyloid deposit, glucose metabolism, cognitive scores and clinical diagnosis. ResultsWe identified 4 clusters that plausibly capture certain stages of AD and organized the clusters in the latent space. The inferred tau trajectory agreed with the Braak staging. According to the derived pseudo-time, tau first deposits in the parahippocampal and amygdala, and then spreads to fusiform, inferior temporal lobe, and posterior cingulate. Prior to the regional tau deposition, amyloid accumulates first. ConclusionThe spatiotemporal trajectory of tau progression inferred in this study was consistent with Braak staging, and the profile of other biomarkers in disease progression agreed well with previous findings. We addressed that this approach additionally carries a potential to quantify tau progression as a continuous variable taking a whole-brain tau image into account.

The Role of Light Kappa and Lambda Chains in Heart Function Assessment in Patients with AL Amyloidosis

There are reports indicating that myocardial dysfunction in systemic immunoglobulin light chain amyloidosis (AL amyloidosis) stems not only from the amyloid deposit in the organ but also the cardiotoxicity of the amyloid precursor free light chains (FLCs) circulating in the blood. The aim of the study is to analyze the role of sFLC κ and λ in the assessment of heart involvement and the degree of myocardial damage in AL amyloidosis. The study involved 71 patients diagnosed with primary AL amyloidosis. The relationship between sFLC concentrations and cardiac biochemical and echocardiographic parameters was assessed. The median concentrations of N-terminal pro b-type natriuretic peptide(NT-proBNP) and troponin I (TnI) were significantly higher in patients with amyloids formed from monoclonal λ chains compared to patients with monoclonal κ proliferation. In patients with heart involvement by amyloids formed from monoclonal FLC, the study demonstrated a statistically significant positive correlation between the concentration of monoclonal antibody λ chain and TnI (R = 0.688; p < 0.05), NT-proBNP (R = 0.449; p < 0.05), and the value of diastolic dimension of the interventricular septum (IVS; R = 0.496, p < 0.05). The above data indicate that the presence of monoclonal λ chains in patients with AL amyloidosis may be associated with more severe damage to cardiomyocytes and dysfunction of the myocardium.

Imaging appearance of the involved mesenteric node in patient with systemic amyloidosis: A case report

Amyloidosis is a rare disease characterised by abnormal amyloid protein deposition within the affected tissue. About 37% of the patients were presented with systemic amyloidosis, of which hilar, mediastinal, and para-aortic lymph nodes were involved. Deposition of amyloid protein in the mesenteric lymph node is rarely documented, but when reported, it is seen in isolated or secondary amyloidosis. Despite an indistinguishable imaging appearance of the amyloid- deposit mesenteric node from malignancy, infection, and an inflammation process, the radiologists should be aware of variable imaging findings to be suspicious of amyloidosis. We reported a rare case of systemic amyloidosis with mesenteric node involvement, manifested as node enlargement.

Neurotropic Grades in Lattice Corneal Dystrophy Based on in Vivo Confocal Microscopy Observation

Background: To investigate the corneal neurotropic phenomenon in patients with lattice corneal dystrophy (LCD) with in vivo laser scanning confocal microscopy (IVCM). Methods: IVCM was performed on a total of 15 patients (28 eyes) with LCD annually at a follow-up. A collection of the data was acquired to be analyzed. Results: As indicated by the analysis, the LCD patients’ normal corneal stromal nerves (Grade 0) presented a decline with the prolongation of the follow-ups, corresponding to a gradual increase in grade I and II involving amyloid-wrapped nerve fibers, which demonstrated that the growing amount of amyloid deposit due to the corneal nerve invasion increased slowly over time. Conclusions: The neurotropic phenomenon could increase with its severity in the corneal lesion of the patients with LCD, and also reflect the distribution of the corneal nerves, to some extent. IVCM provides a rapid, noninvasive way to observe the corneal nerves, which can be an efficient means of better understanding the development of LCD.

Induction of amyloid-β deposits from serially transmitted, histologically silent, Aβ seeds issued from human brains

In humans, iatrogenic transmission of cerebral amyloid-β (Aβ)-amyloidosis is suspected following inoculation of pituitary-derived hormones or dural grafts presumably contaminated with Aβ proteins as well as after cerebral surgeries. Experimentally, intracerebral inoculation of brain homogenate extracts containing misfolded Aβ can seed Aβ deposition in transgenic mouse models of amyloidosis or in non-human primates. The transmission of cerebral Aβ is governed by the host and by the inoculated samples. It is critical to better characterize the propensities of different hosts to develop Aβ deposition after contamination by an Aβ-positive sample as well as to better assess which biological samples can transmit this lesion. Aβ precursor protein (huAPPwt) mice express humanized non-mutated forms of Aβ precursor protein and do not spontaneously develop Aβ or amyloid deposits. We found that inoculation of Aβ-positive brain extracts from Alzheimer patients in these mice leads to a sparse Aβ deposition close to the alveus 18 months post-inoculation. However, it does not induce cortical or hippocampal Aβ deposition. Secondary inoculation of apparently amyloid deposit-free hippocampal extracts from these huAPPwt mice to APPswe/PS1dE9 mouse models of amyloidosis enhanced Aβ deposition in the alveus 9 months post-inoculation. This suggests that Aβ seeds issued from human brain samples can persist in furtive forms in brain tissues while maintaining their ability to foster Aβ deposition in receptive hosts that overexpress endogenous Aβ. This work emphasizes the need for high-level preventive measures, especially in the context of neurosurgery, to prevent the risk of iatrogenic transmission of Aβ lesions from samples with sparse amyloid markers.

Prognostication of cardiac amyloidosis by pittsburgh b compound positron emission tomography

Introduction Regardless of the underlying pathogenesis of amyloid production, cardiac involvement is the leading cause of morbidity and mortality in systemic amyloidosis. In the cardiac variant, there is an extracellular deposition of amyloid substance throughout the heart. The infiltrative process results in ventricular wall thickening with concentric hypertrophy and low cardiac output. The PiB compound has been promising for the detection of amyloid deposits in the brain but it remains unknown whether this noninvasive evaluation can predict the prognosis of patients with cardiac amyloidosis. Purpose This study sought to investigate the efficacy of 11C-Pittsburgh B (PiB) positron emission tomography for prognostication of cardiac amyloidosis by noninvasively imaging the myocardial amyloid deposition. Methods A total of 33 consecutive patients were enrolled in this prospective pilot study with suspected cardiac amyloidosis. The amyloid deposit was assessed with amyloid P immunohistochemistry in endomyocardial biopsy specimens and was compared with the degree of myocardial 11C-PiB uptake on PET. Results It was found that the degree of myocardial 11C-PiB PET uptake was significantly greater in the patients of cardiac amyloidosis compared with control group subjects and was parallel with the degree of amyloid deposit on histology (p&lt;0.001). When the cardiac amyloidosis patients were divided into tertiles by the degree of myocardial 11C-PiB PET uptake, patients with the highest PiB uptake experienced the worst clinical event-free survival (log-rank p=0.013). The clinical outcome was significantly predicted by the degree of myocardial PiB PET uptake on multivariate Cox regression analysis (adjusted hazard ratio: 1.191; 95% confidence interval: 1.062 to 1.340; p=0.005). Conclusion Our study concludes that the noninvasive evaluation of myocardial amyloid load by 11C-PiB PET reflects the degree of amyloid deposit and is an independent predictor of clinical outcome in cardiac amyloidosis patients. 11-C Pittsburgh B PET imaging Funding Acknowledgement Type of funding source: Other. Main funding source(s): Self funding

Synapsin-caveolin-1 mitigates cognitive deficits and neurodegeneration in Alzheimer’s disease mice

ABSTRACTAD presents with severe neurodegeneration which leads to cognitive deficits and dementia. Identifying the molecular signals that attenuate neurodegeneration in AD may be exploited as therapeutic targets. This study revealed that transgenic AD mice (PSAPP) exhibit decreased caveolin-1 (Cav-1), a membrane/lipid raft (MLR) scaffolding protein that organizes synaptic signaling components. Subcellularly, Cav-1 and full length (fl)-TrkB were significantly decreased in MLRs. We thus developed an in vivo gene therapy that re-expresses neuronal-targeted Cav-1 using the synapsin promoter (SynCav1). While AD mice showed significant learning and memory deficits at 9 and 11 months, AD mice that received hippocampal SynCav1 (AD-SynCav1) maintained normal learning and memory at 9 and 11 months respectively. Furthermore, AD-SynCav1 mice showed preserved hippocampal MLR-localized fl-TrkB, synaptic ultrastructure, dendritic arborization and axonal myelin content, all of which occurred independent of reducing amyloid deposit and astrogliosis. Thus, SynCav1 demonstrates translational potential to treat AD by delaying neurodegeneration.SummaryTransgenic PSAPP mice exhibit decreased hippocampal expression of the membrane lipid raft (MLR) scaffolding protein caveolin-1. Synapsin-promoted re-expression of Cav-1 (termed SynCav1) mitigated neuropathology and cognitive deficits. SynCav1 gene therapy has the potential to treat AD and other forms of neurodegeneration.